The cerebral cortex mediates perceptions and motor control by receiving and sending information through the thalamus. Some neurological disorders such as mental retardation, epilepsy, and schizophrenia appear to involve developmental defects in the wiring of the cerebral cortex. Molecular mechanisms of thalamocortical axon (TCA) development will be studied by taking a forward genetics approach. Specific Aim I: To peform a screen for mouse mutants with defects in thalamocortical development, using a specific reporter. The TCA-TLZ (thalamocortical axon-tau-lacZ) reporter line allows visualization of TCAs in whole brains without slicing, and therefore provides a unique tool with which to rapidly screen for defects in thalamocortical development. The reporter line will be mutagenized and the brains of third-generation progeny at embryonic day 18 will be analyzed for defects. Screening embryos will enable recovery of lethal mutations. This reporter will reveal defects in thalamic axon guidance and cortical lamination. Specific Aim Il: To characterize the phenotypes of mutants identified in the screen. Mutant brains will be examined at several developmental stages using the tau-lacZ marker as well as standard neuroanatomical and histological methods to determine the extent and cause of the phenotypes observed. Specific Aim Ill: To positionally clone one or two genes identified in the screen that represent the most interesting phenotypes and novel loci. After high resolution mapping, candidate genes will be examined by expression and sequencing of exons from the mutants to find the mutations. The Candidate has an excellent record so far as a neuroscientist, but wishes to receive additional training in mouse genetics before starting an independent laboratory to study the molecular mechanisms underlying cortical development. In the Ph.D., C. elegans genetics was used to study how neurons target proteins to specific membrane domains. A transition was made to the rodent system to study cortical development using histological and neuroanatomical techniques. To add mouse genetics to the skill set, the candidate has arranged to work jointly with Dr. Christopher Walsh and Dr. David Beier, both at Harvard Medical School. Combining the expertise in mouse genetics with the previous training in mouse neuroanatomy and nematode genetics will significantly add to the Candidate's potential to make a strong impact on the field.